Development of novel lung cancer therapeutics targeting the DNA damage response. Abstract Lung tissue is constantly exposed to a wide variety of inhaled chemical agents. While the majority of these maybe innocuous, those that damage DNA have severe consequences. Thus, the DNA damage response (DDR) and DNA repair in these tissues is extremely important. The vast majorities of lung cancers are diagnosed in older individuals and can be attributed to complications from tobacco smoke exposure where it has been estimated that one mutation is generated for every 15 cigarettes smoked. While we have made significant strides in treatment options for non-smoking lung cancer patients with identifiable driver mutations, there have been relatively few advances in treatment of smoking-induced lung cancers. The research in this phase I STTR application exploits two important, novel findings. The first is data we recently obtained demonstrating that lung cancer patients treated with adjuvant cisplatin chemotherapy after surgery with high XPA (xeroderma pigmentosum group A) expression correlates with a decrease in overall survival. This correlation is unique to XPA and not observed with other DNA repair genes, consistent with XPA being the limiting factor in nucleotide excision repair (NER). These preliminary data serves as the rationale for targeting XPA for adjuvant combination therapy in this patient population. The second advance driving this research is our recent development of novel XPA inhibitors (XPA inhibitors). We originally identified XPA inhibitors with modest activity (IC50's of 50-100 M) an have recently developed derivatives with IC50's in the nM range. In a single aim, we will exploit our recently discovered structure activity relationships (SAR) to complete lead optimization to maximize bioavailability, potency and specificity of XPA inhibitors. We then will interrogate the i vivo effects including PK/PD, toxicity and efficacy. Completion of these studies will provide essential information for IND enabling studies towards the development of a novel therapeutic treatment for smoking- induced lung cancer.